Discovery of Oxidized p-Terphenyls as Phosphodiesterase 4 Inhibitors from Marine-Derived Fungi

  • J Nat Prod. 2024 Jun 29. doi: 10.1021/acs.jnatprod.4c00422.
Jian Cai  1  2 ,  Qian Zhou  3  4 ,  Xin Qi  5 ,  Furong Zhang  3  4 ,  Jiafan Yang  1  2 ,  Chunmei Chen  1  2 ,  Kai Zhang  3  4 ,  Zhexin Chen  3  4 ,  Hai-Bin Luo  3  4 ,  Yonghong Liu  1 ,  Yi-You Huang  3  4 ,  Xuefeng Zhou  1  2
Affiliations
  • 1. CAS Key Laboratory of Tropical Marine Bio-resources and Ecology/Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou 510301, China.
  • 2. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 3. Key Laboratory of Tropical Biological Resources of Ministry of Education and Hainan Engineering Research Center for Drug Screening and Evaluation, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 4. Song Li' Academician Workstation of Hainan University (School of Pharmaceutical Sciences), Yazhou Bay, Sanya 572000, China.
  • 5. Wuya College of Innovation, Shenyang Pharmaceutical University, Shenyang 110016, China.
PMID: 38943602 DOI: 10.1021/acs.jnatprod.4c00422
Abstract

Four new p-terphenyl derivatives, talaroterphenyls A-D (1-4), together with three biosynthetically related known ones (5-7), were obtained from the mangrove sediment-derived Talaromyces sp. SCSIO 41412. Compounds 1-3 are rare p-terphenyls, which are completely substituted on the central benzene ring by oxygen atoms; this is the first report of their isolation from natural sources. Their structures were elucidated through NMR spectroscopy, HRESIMS, and X-ray diffraction. Genome sequence analysis revealed that 1-7 were biosynthesized from tyrosine and phenylalanine, involving four key biosynthetic genes (ttpB-ttpE). These p-terphenyls (1-7) and 36 marine-derived terphenyl analogues (8-43) were screened for phosphodiesterase 4 (PDE4) inhibitory activities, and 1-5, 14, 17, 23, and 26 showed notable activities with IC50 values of 0.40-16 μM. The binding pattern of p-terphenyl inhibitors 1-3 with PDE4 were explored by molecular docking analysis. Talaroterphenyl A (1), with a low cytotoxicity, showed obvious anti-inflammatory activity in LPS-stimulated RAW264.7 cells. Furthermore, in the TGF-β1-induced medical research council cell strain-5 (MRC-5) pulmonary fibrosis model, 1 could down-regulate the expression levels of FN1, COL1, and α-SMA significantly at concentrations of 5-20 μM. This study suggests that the oxidized p-terphenyl 1, as a marine-derived PDE4 Inhibitor, could be used as a promising antifibrotic agent.

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